Organellar (Na+, K+)/H+ exchanger NHE7 regulates cell adhesion, invasion and anchorage-independent growth of breast cancer MDA-MB-231 cells

Abstract

Abstract. Na+ /H + exchangers (NHEs) are a group of secondary active antiporters that regulate cellular pH, cell volume and ion homeostasis. In humans, nine isoforms (NHE1-NHE9) were identified and characterized as functional NHEs. While a growing body of evidence indicates that NHE1 generates an acidic tumor environment and thereby contributes to tumor invasion, little is known about the role of other NHE isoforms in tumor progression. NHE7 is a unique member of the NHE gene family that dynamically shuttles between the trans-Golgi network, endosomes and the plasma membrane, and regulates the luminal pH of these organelles. Here we show that NHE7-overexpression in breast cancer MDA-MB-231 cells enhances cell overlay, cell-cell adhesion, invasion, anchorage-independent tumor growth and tumor formation in vivo. In contrast, NHE1-overexpression enhances tumor invasion, but it has little effect on cell adhesion or anchorageindependent tumor growth. Pathological examinations of the tumor samples derived from NHE7-overexpressing cells showed a similar appearance to aggressive tumors. Together, these results suggest that NHE7 enhances tumor progression. This is the first report to show the involvement of an organellar NHE in oncogenic processes.

A leak pathway for luminal protons in endosomes drives oncogenic signalling in glioblastoma

“…Despite these clinical and genetic links, the molecular role of NHE9 in carcinogenesis was previously unknown. There has been one report showing that ectopic expression of NHE7, a closely related isoform of NHE9 that localizes to the trans -Golgi network, increased tumorigenicity in a breast cancer cell line 32 . Although the underlying mechanisms were not investigated, the study showed that whereas tumor invasion was enhanced by both NHE1 and NHE7, only NHE7 could promote anchorage-independent growth and cell-adhesion.…”

Extracellular Alkaline pH Leads to Increased Metastatic Potential of Estrogen Receptor Silenced Endocrine Resistant Breast Cancer Cells

“…As these pumps expel H + to the extracellular environment, increasing acidity, their inhibition should increase contractolation . Either these agents are affecting some other process or the NHE and ATPase have other functions in non- excitable cells distinct from ion regulation [68,69,70]. …”

Differential Expression of Na+/H+-Exchanger (NHE-1, 2, and 4) Proteins and mRNA in Rodent’s Uterus under Sex Steroid Effect and at Different Phases of the Oestrous Cycle

“…NHE is involved in cell volume changes and intracellular pH regulations as well as acid-base balance [4, 5]. Its activity also facilitates cellular adhesion, migration, and proliferation [6]. NHE plays an important role in many absorptive and secretory epithelia.…”